Methods of use of ultra-high dose rate radiation and therapeutic agent

Abstract

Methods for treating tumors by administering FLASH radiation and a therapeutic agent to a patient with cancer are disclosed. The methods provide the dual benefits of anti-tumor efficacy plus normal tissue protection when combining therapeutic agents with FLASH radiation to treat cancer patients. The methods described herein also allow for the classification of patients into groups for receiving optimized radiation treatment in combination with a therapeutic agent based on patient-specific biomarker signatures. Also provided are radiation treatment planning methods and systems incorporating FLASH radiation and therapeutic agents.

What is claimed is: 
     
       1. A method of identifying a subject with cancer as a candidate for a treatment comprising ultra-high-dose-rate radiation (FLASH RT) and a therapeutic agent, the method comprising:
 (a) determining an expression level of one or more biomarkers in a tumor sample from the subject, wherein the one or more biomarkers are selected from the group consisting of an immune cell marker, a tumor cell marker, a circulating marker, an imaging marker, and any combination thereof; 
 (b) comparing the expression level of the one or more biomarkers in the tumor sample to an expression level of the one or more biomarkers in a normal tissue sample; and 
 (c) classifying the subject as a candidate for a treatment comprising FLASH RT and the therapeutic agent if the expression level of the one or more biomarkers in the tumor sample is modified compared to the expression level of the one or more biomarkers in the normal tissue sample. 
 
     
     
       2. The method of  claim 1 , wherein the one or more biomarkers are selected from the group consisting of CD44, MMP9, ALDH1A1, Vimentin, hyaluronan, beta-catenin, MFG-E8, CD68, TGFβ, a TGFβ-pathway related biomarker, or any combination thereof. 
     
     
       3. The method of  claim 1 , wherein the tumor sample is a biopsy comprising tumor cells. 
     
     
       4. The method of  claim 1 , wherein the normal tissue sample comprises non-tumor cells from the same tissue type as the subject's cancer. 
     
     
       5. The method of  claim 1 , wherein the therapeutic agent is an immune modulator agent. 
     
     
       6. The method of  claim 1  further comprising contacting the subject's cancer with a radiosensitizer. 
     
     
       7. A method of selecting a treatment for a subject with cancer, the method comprising:
 (a) determining an expression level of one or more biomarkers in a tumor sample from the subject, wherein the one or more biomarkers are selected from the group consisting of an immune cell marker, a tumor cell marker, a circulating marker, and any combination thereof; 
 (b) comparing the expression level of the one or more biomarkers in the tumor sample to an expression level of the one or more biomarkers in a normal tissue sample; and 
 (c) selecting a treatment comprising FLASH RT and a therapeutic agent if the expression level of the one or more biomarkers in the tumor sample is modified compared to the expression level of the one or more biomarkers in the normal tissue sample. 
 
     
     
       8. The method of  claim 7 , wherein an effective dose of FLASH RT is increased from a current effective dose if the subject is already undergoing a radiation therapy for a tumor. 
     
     
       9. The method of  claim 7 , wherein an effective dose of FLASH RT administered to a tumor is increased if the expression level of the one or more biomarkers is elevated in a tumor environment.